Hazardous giant pharyngoesophageal liposarcoma.

A man in his early 80s presented to the otorhinolaryngology department with progressively worsening dysphagia to solids and a recent episode of difficulty breathing accompanied by a very brief expulsion of a solid mass from the mouth. Based on the endoscopic appearance of a fatty lesion of an elongated mass with a thick stalk on the posterior pharyngeal wall, a diagnosis of the benign fibrovascular polyp was given after clinical and radiological correlation. The pharyngeal polyp was resected at the base of its pedicle by transoral endoscopy with a thunder beat vessel sealing device. Histopathological examination of the mass revealed a well-differentiated liposarcoma composed of mature adipocytes. Following surgical excision, the patient made a full recovery. This case signifies the integrated role of preoperative biopsy, new surgical technologies and targeted therapies in managing pharyngoesophageal polyps.

Optimizing variant-specific therapeutic SARS-CoV-2 decoys using deep-learning-guided molecular dynamic simulations. (preprint)

Treatment of COVID-19 with a soluble version of ACE2 that binds to SARS-CoV-2 virions before they enter host cells is a promising approach, but it needs to be optimized and adapted to emerging viral variants. The computational workflow presented here consists of molecular dynamics simulations for RBD-ACE2 binding affinity assessments of ACE2 or RBD variants and a novel convolutional neural network architecture working on pairs of voxelized force-fields for efficient search-space reduction. We identified hACE2-Fc K31W along with multi-mutation variants as high-affinity candidates, which we also validated in vitro with virus neutralization assays. We evaluated binding affinities of these ACE2 variants with the RBDs of Omicron BA.3, Omicron BA.4/BA.5, and Omicron BA.2.75 in silico. In addition, candidates produced in Nicotiana benthamiana, an expression organism for potential large-scale production, showed a 4.6-fold reduction in half-maximal inhibitory concentration (IC50) compared with the same variant produced in CHO cells and an almost six-fold IC50 reduction compared with wild-type hACE2-Fc.

Changes in the mutational dynamics of the SARS-CoV-2 main-protease substantiate the danger of emerging resistance to antiviral drugs. (preprint)

The current coronavirus pandemic is being combated worldwide by nontherapeutic measures and massive vaccination programs. Nevertheless, therapeutic options such as SARS-CoV-2 main-protease (Mpro) inhibitors are essential due to the ongoing evolution toward escape from natural or induced immunity. While antiviral strategies are vulnerable to the effects of viral mutation, the relatively conserved Mpro makes an attractive drug target: Nirmatrelvir, an antiviral targeting its active site, has been authorized for conditional or emergency use in several countries since December 2021, and a number of other inhibitors are under clinical evaluation. We analyzed recent SARS-CoV-2 genomic data and discovered accelerated mutational dynamics in an eight-residue long consecutive region (R188-G195) near the active site of Mpro since early December 2021. The herein described increased mutational variability in close proximity to an antiviral-drug binding site may suggest the onset of the development of antiviral resistance. This emerging diversity urgently needs to be further monitored and considered in ongoing drug development and lead optimization.

Intrusion Detection System: A Comparative Study of Machine Learning-based IDS (preprint)

Due to the Covid-19 pandemic, there has been a significant rise in the amount of data processed and transferred to any communication network. The use of encrypted data, the diversity of new protocols, and the surge in the number of malicious activities worldwide have posed new challenges for Intrusion Detection Systems (IDS). In this scenario, existing signature-based IDS are not performing well. Various researchers have proposed machine learning-based IDS to detect unknown malicious activities based on behaviour patterns. Results have shown that machine learning-based IDS perform better than signature-based IDS (SIDS) in identifying new malicious activities in the communication network. In this paper, we have analyzed the IDS dataset that contains the most current common attacks and evaluated the performance of network intrusion detection systems by adopting two data resampling techniques and ten machine learning classifiers. It has been observed that the top three IDS models KNeighbors, XGBoost and AdaBoost outperform in binary-class classification with 99.49%, 99.14% and 98.75% accuracy, and XGBoost, KNneighbors, and GaussianNB outperform in multi-class classification with 99.30%, 98.88% and 96.66% accuracy, respectively.

Tele-yoga in the management of Ankylosing Spondylitis amidst COVID pandemic: A Prospective Randomized Controlled Trial (preprint)

Patients with Ankylosing Spondylitis (AS) often report mental and physical problems and have a poor quality of life (QoL). This study intended to investigate the efficacy of a 3-months tele-yogic intervention on the disease activity, inflammatory markers, and mental health measures in patients with AS. Hundred and twenty AS patients were assigned to either the yoga intervention or control arm. The yoga intervention arm (YG) (n = 57) received a 60-minutes structured yoga module for 3-months on online in addition to standard medical care. The control (CG) participants (n = 52) followed only standard care for the same period. BASDAI, BASFI, ASQOL, psychological and inflammatory biomarkers were assessed at baseline and three months. YG showed significant improvement in BASDAI (p = 0.001), anxiety (p = 0.0004), and depression (p = 0.001) at 3-months compared to the baseline. The CG showed no change. After 3-months, the intervention resulted in a significant improvement in BASDI (-0.79; 95% CI (-1.3, to -0.29); p = 0.0021),BASFI (-0.86; 95% CI (-1.59, to -0.14); p = 0.0193), anxiety (-0.42; 95% CI (-0.84 to -0.01); p = 0.0468), and AS-QoL (-3.37; 95% CI (-5.21, to 1.53); p = 0.0004) compared to the CG. The present study suggests that Yoga helps to improve the pain, functional index, and mental health among patients with AS. The tele-yoga intervention is feasible and effective in the management of AS.

Significant Broad Spectrum Antiviral activity of Bi121 Against Different Variants of SARS-CoV-2 (preprint)

The SARS-CoV-2 pandemic infected 343 million people with over 5.59 million deaths. New mutated lineages of SARS-CoV-2 such as Omicron are evolving faster. Broad-spectrum viral inhibitors that block the initial stage of infection by reducing virus proliferation and disease severity is an unmet global medical need. We studied Bi121, a standardized polyphenolic-rich compound isolated from Pelargonium sideodes, against recombinant Vesicular Stomatitis Virus (rVSV)-pseudotyped SARS-CoV-2S (spike) that represent mutations in the spike protein of six different variants of SARS-CoV-2. Bi121 was effective in neutralizing all six rVSV-{Delta}G-SARS-CoV-2S variants expressing different mutations. The antiviral activity of Bi121 was then assessed against three variants of SARS-CoV-2 (USA WA1/2020, Hongkong/VM20001061/2020, B.1.167.2 (Delta)) using RT-qPCR and plaque assays in two different cell lines (Vero cells and HEK-ACE2). Bi121 showed significant activity toward all the three variants tested, suggesting a broad-spectrum activity.

Structural-bioinformatics analysis of SARS-CoV-2 variants reveals higher hACE2 receptor binding affinity for Omicron B.1.1.529 spike RBD compared to wild-type reference. (preprint)

To date, more than 263 million people have been infected with SARS-CoV-2 during the COVID-19 pandemic. In many countries, the global spread came in several pandemic waves characterized by the emergence of new SARS-CoV-2 variants. Here, we report on a sequence- and structural-bioinformatics analysis by which we estimate the impact of amino acid exchanges on the affinity of the SARS-CoV-2 spike receptor-binding domain (RBD) to the human receptor hACE2. This is carried out by qualitative electrostatics and hydrophobicity analysis as well as through molecular dynamics simulations used for the development of a highly accurate linear interaction energy (LIE) binding affinity model that was calibrated on a large set of experimental binding energies. For the newest variant of concern (VOC), B.1.1.529 Omicron, our Halo difference point cloud studies reveal the largest impact on the RBD binding interface compared to any other VOC. Moreover, according to our LIE model, Omicron achieved a substantially higher ACE2 binding affinity than the wild-type and in particular the highest among all VOCs except for Alpha and therefore requires special attention and monitoring. Using this prediction model we provide early structural insight and binding properties before experimentally determined complex structures and binding affinity data become available in the upcoming months.

Effect of prone positioning and high flow nasal oxygen on oxygenation and overall outcome in spontaneously breathing awake patient with severe COVID-19 induced acute hypoxemic respiratory failure: A prospective observational study

Background Previous studies suggest that prone positioning can increase PaO2/FiO2 and reduce mortality in moderate to severe acute respiratory distress syndrome. Effect of prone positioning and high flow nasal oxygen has been studied individually in COVID-19 patients but their combined effect on patient's outcome is yet to be reported. Methods In this study 120 severe COVID-19 positive patients were included and placed in awake prone positioning with high flow nasal oxygen. The efficacy in improving oxygenation with prone positioning and high flow nasal oxygen were evaluated by blood gas analysis. The primary outcome was a proportion of patients requiring non-invasive ventilation or invasive ventilation. The secondary outcomes were a comparison of arterial blood gas parameters and biochemical inflammatory parameters pre proning, end of first proning and end of last prone position in these patients. Results We found only 35 patients (34.3%) required the need for non-invasive or invasive mechanical ventilation support whereas 67 patients (65.7%) were managed successfully on high flow nasal oxygen along with awake prone positioning (p = 0.001). We found there were statistically significant improvements in arterial blood gas parameters and biochemical inflammatory markers after the end of last prone positioning with high flow nasal oxygen. Conclusions Early application of prone positioning in combination with high flow nasal oxygen may help in avoiding mechanical ventilation by improving oxygenation and biochemical inflammatory markers.

Changing To Removable Casts During The Coronavirus Pandemic – Has It Affected Outcomes For Distal Radius Fractures? (preprint)

Background: BOAST (British Orthopaedic Association Standards for Trauma & Orthopaedics) guidelines recommended that during the coronavirus pandemic most upper limb fractures should be treated conservatively, and removable casts should be used, where possible. As a result, our district general hospital started using a new soft combination (soft-combi) casting technique for conservative management of distal radius fractures (DRFs) in an attempt to reduce follow-up attendances.Aims: To assess if radiological outcomes of soft-combi casts are better or worse than previously used rigid casts for DRFs.Methods: 20 DRFs treated with soft-combi casts were compared with 20 DRFs treated with the old rigid cast types. Radiological parameters were measured pre-manipulation, post-manipulation, at 2-week follow-up, and at final follow-up. Statistical analysis was performed to assess for significant differences seen at follow-up between the groups.Results: The mean loss of volar angulation seen at 2-week follow-up was 4.9 degrees for the rigid casts vs. 1.5 degrees for the soft-combi casts (p=0.158). The mean loss of radial height after 2 weeks was 0.2 mm vs 0.5 mm (p=0.675), and the mean loss of radial inclination was 2.0 degrees vs 1.0 degrees (p=0.349), respectively.Conclusion: The soft-combi casts appeared to be equally effective at maintaining the reduction of DRFs compared to their rigid counterparts, as no statistically significant difference was seen in our study. We can be reassured that continued use of these removable casts in the current climate is unlikely to have a detrimental effect on outcomes for DRFs.

SARS-CoV-2 Entry Protein TMPRSS2 and Its Homologue, TMPRSS4 Adopts Structural Fold Similar to Blood Coagulation and Complement Pathway Related Proteins (preprint)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes TMPRSS2 receptor to enter target human cells and subsequently causes coronavirus disease 19 (COVID-19). TMPRSS2 belongs to the type II serine proteases of subfamily TMPRSS, which is characterized by the presence of the serine-protease domain. TMPRSS4 is another TMPRSS member, which has a domain architecture similar to TMPRSS2. TMPRSS2 and TMPRSS4 have been shown to be involved in SARS-CoV-2 infection. However, their normal physiological roles have not been explored in detail. In this study, we analyzed the amino acid sequences and predicted 3D structures of TMPRSS2 and TMPRSS4 to understand their functional aspects at the protein domain level. Our results suggest that these proteins are likely to have common functions based on their conserved domain organization. Furthermore, we show that the predicted 3D structure of their serine protease domain has significant similarity to that of plasminogen which dissolves blood clot, and of other blood coagulation related proteins. Additionally, molecular docking analyses of inhibitors of four blood coagulation and anticoagulation factors show the same high specificity to TMPRSS2 and TMPRSS4 3D structures. Hence, our observations are consistent with the blood coagulopathy observed in COVID-19 patients and their predicted functions based on the sequence and structural analyses offer avenues to understand better and explore therapeutic approaches for this disease.

A prospective observational safety study on ChAdOx1 nCoV- 19 corona virus vaccine (recombinant) use in healthcare workers- first results from India (preprint)

Vaccines are an important public health measure for tiding over the COVID-19 pandemic. Several vaccines have been approved in different countries for emergency use. In India, two vaccines have been currently approved- COVISHIELD (Serum Institute of India (SII)) which is a recombinant simian adenovirus-based vaccine and COVAXIN (Bharat Biotech) which is an inactivated SARS-CoV-2 vaccine. Our current study provides the first post approval safety data on ChAdOx1 nCoV- 19 corona virus vaccine (recombinant) use in healthcare workers in northern India (n=804). Around one half of vaccinees developed adverse events at any time post vaccination with majority of reactions being mild to moderate in severity. AEFIs were seen in 40% participants after first dose and around 16% participants after second dose. This observed reactogenicity is much less compared to 60-88% reactogenicity rate observed with Oxford-AstraZenecas ChAdOx1 vaccine in the UK based population. Individually, fever, injection site pain and headache were the commonly observed AEFIs. Overall, the frequency of systemic events of severity grade 3 was only 0.5% and is much less than the reported rates for other recombinant adenoviral vaccines. The rate of serious AEFIs in our study was only 0.1% (n=1). There was a possibility of this AEFI being an immunization stress related response. No deaths were reported in the vaccinees in our study during the study period. Reactogenicity rate was observed to decrease with age and was higher in females. On the basis of interim findings of this safety study, it may be interpreted that the ChAdOx1 nCoV-19 corona virus vaccine (recombinant) (COVISHIELD, Serum Institute of India) carries a good safety profile overall.

The Impact of the Coronavirus Pandemic on Patients With Acute Proximal Femoral Fracture: a Retrospective, Observational, Cohort Study (preprint)

• Background – During the initial peak of the COVID-19 pandemic in the United Kingdom (UK) admissions related to acute proximal femoral fracture (APFF) remained consistent.• Aims – This aim of this research is to demonstrate the impact of the COVID-19 pandemic on this cohort of high-risk patients and provide revenues for improvement in their care as we globally progress through further peaks of viral transmission and illness.• Methods– Retrospective, observational, cohort study of 112 patients with APFF; sustained during the first peak of the pandemic (1st March – 15th May, 2020). Following ethical approval, data was collected from electronic records. Included patients were those who had been admitted to one of two district general hospitals in Northwest England. Only patients with APFF were included – chronic, peri-prosthetic, femoral shaft and open fractures were excluded. Patients were split into two groups: COVID-positive (N = 17) and COVID-negative (N = 95) with the primary outcome measure being 30-day mortality.• Results – 17.9% overall mortality (29.4% for COVID-positive and 15.7% for COVID-negative). The odds ratio for mortality was 2.2 in the COVID-positive group compared to the COVID-negative group (95% confidence level; 0.68–7.23).• Conclusions – Patients with APFF suffered increased mortality during the initial peak of the COVID-19 pandemic. However, increased mortality in COVID-positive patients, compared to the COVID-negative patients, was not statistically significant. Increased mortality in COVID-negative patients may have been due to other pandemic related factors including: undiagnosed COVID-19; patient demographics and the effects of changes to the service provision structure of the orthopaedic department during this time. Moving forward, as the global fight against COVID-19 continues, we provide the below recommendations as suggested revenues to improve 30-day mortality for these patients during pandemic times:• repeated COVID-19 testing for all APFF patients;• strict separation of COVID-suspected, COVID-positive, and COVID-negative patients;• preservation of acute trauma services, including protected theatre time; and• maintenance of experienced orthopaedic teams on wards throughout periods of re-deployment.Further research with larger sample sizes is needed to assess the national and international applicability of these recommendations.

Serine 477 plays a crucial role in the interaction of the SARS-CoV-2 spike protein with the human receptor ACE2. (preprint)

Since the worldwide outbreak of the infectious disease COVID-19, several studies have been published to understand the structural mechanism of the novel coronavirus SARS-CoV-2. During the infection process, the SARS-CoV-2 spike (S) protein plays a crucial role in the receptor recognition and cell membrane fusion process by interacting with the human angiotensin-converting enzyme 2 (hACE2) receptor. However, new variants of these spike proteins emerge as the virus passes through the host reservoir. This poses a major challenge for the design of a potent antibody against these spike proteins. Through structural bioinformatics analysis based on normal mode analysis (NMA) we identified a highly flexible region in the receptor binding domain (RBD) of SARS-CoV-2, starting from residue 475 up to residue 485. Structurally, S477 shows the highest rotational degrees of freedom among them. At the same time, S477 is the world’s most frequently mutated residue in the RBD of SARS-CoV-2. Therefore, using advanced MD simulations, we have investigated the role of S477 and its two frequent mutations (S477G and S477N) at the RBD during the binding to hACE2. We found that the amino acid exchanges S477G and S477N strengthen the binding of the SARS-COV-2 spike with the hACE2 receptor.

Transaminitis is an indicator of mortality in patients with COVID-19: A retrospective cohort study.

BACKGROUND: Since its discovery in Wuhan, China in December of 2019, the novel coronavirus has progressed to become one of the worst pandemics seen in the last 100 years. Recently, there has been an increased interest in the hepatic manifestations of coronavirus disease 19 (COVID-19). AIM: To describe the demographic and clinical characteristics of COVID-19 positive patients and study the association between transaminitis and all-cause mortality. METHODS: This is a descriptive retrospective cohort study of 130 consecutive patients with a positive COVID PCR test admitted between March 16, 2020 to May 14, 2020 at a tertiary care University-based medical center. The Wilcoxon-rank sum test and paired t-test were used for comparing non-parametric and parametric continuous variables respectively and a multivariable logistic regression models to study the association between transaminitis and mortality using SAS version 9.4 (SAS Institute, Cary, NC, United States). RESULTS: Out of the 130 patients, 73 (56%) patients were found to have transaminitis and 57 (44%) did not. When compared to patients without transaminitis, the transaminitis group was found to have a higher median body mass index (30.2 kg/m2 vs 27.3 kg/m2, P = 0.04). In the multivariate analysis those with transaminitis were found to have 3.4 times higher odds of dying as compared to those without transaminitis adjusting for gender, the Age-adjusted Charlson Comorbidity Index and admission to the intensive care unit (P = 0.03). CONCLUSION: Our study showed that transaminitis on admission was associated with severe clinical outcomes such as admission to the intensive care unit, need for mechanical ventilation, and mortality.

Of Cross-Immunity, Herd Immunity and Country-Specific Plans: Experiences from COVID-19 in India (preprint)

India has witnessed a high number of COVID-19 cases, but mortality has been quite low, and most cases have been asymptomatic or mild. In early April, we had hypothesized a low COVID-19 mortality in India, based on the concept of cross-immunity. The presence of cross-immunity is presumed to lead to a milder course of disease and allow the time necessary for the development of adaptive immunity by the body to eliminate the virus. Evidence supporting our hypothesis has started showing up. Multiple studies have shown the generation of different T cell subsets and B cells responding to epitopes of viral proteins, especially of the spike protein, as a part of adaptive immunity against SARS-CoV-2. Cross-reactive T-cells have been demonstrated in patients who have been previously exposed to endemic coronaviruses. The interplay of cross-immunity and herd immunity is apparent in the COVID-19 scenario in India by the presence of a large number of asymptomatic or mild cases, a low infection-fatality ratio and a generally flat curve of percentage positivity of cases with respect to total testing, both in periods of strict lock-down and step-wise unlocking. It seems that cross-immunity resulted in faster generation of herd immunity. Although the initial restrictive measures such as lockdown prevented the rapid spread of the outbreak, further extension of such measures and overly expensive ones such as enhanced testing in India will result in a huge burden on the health economics as well as the society. Hence, we propose a restructuring of the health services and approach to COVID-19. The restructured health services should move away from indiscriminate testing, isolation and quarantine, and instead, the emphasis should be on improving facilities for testing and management of only critical COVID cases and the replacement of complete lockdowns by the selective isolation and quarantine of the susceptible persons such as the aged and those with co-morbidities. In the process of describing India-specific plans, we emphasize why the development of country-specific plans for tackling epidemics is important, instead of adopting a “one policy fits all” approach.